Adult Clinical Trials Research Articles

FDA analysis of enrollment of older adults in clinical trials for cancer drug registration: A 10-year experience by the U.S. Food and Drug Administration.

10009 Background: Older adults are a growing segment of our oncology population, with an expected increase in cancer incidence of 67% from 2010 to 2030 in people age 65 and older. However, older adults have been proportionally underrepresented in clinical trials. We sought to analyze the age-related enrollment of cancer patients onto trials supporting registration of new drugs or new indications approved by the US Food and Drug Administration from 2005 to 2015. Methods: This study involved retrospective analyses of demographic data of cancer patients enrolled onto trials supporting registration from 2005-2015. The data on 224,766 cancer patients supporting 105 drug applications were analyzed according to age distributions of <65, 65-69, 70-74, 75-79, and ≥80 years. The rates of enrollment were compared with the corresponding rates in the US cancer population. The age distributions of the US cancer population were derived from the Surveillance, Epidemiology, and End Results Program of the National Cancer Institute for the year 2013 based on the 2010 US Census. Conclusions: Older adults were under-represented in the registration trials of new cancer therapies, especially those over age 75. Various strategies may be needed to evaluate cancer therapies for older adults in prospective clinical trials and to improve cancer care in adults over age 75. These include re-evaluating what may be considered restrictive eligibility criteria so as not to exclude older adults. Incorporating elements from geriatric assessment tools may help identify older adults most likely to benefit from treatment. More detailed labeling information that reflects the clinical experience with older adults could be considered. The FDA encourages drug sponsors as well as clinical trial cooperative groups to devise strategies to recruit patients that are reflective of their intended population. [Table: see text]

Dosing immunotherapy combinations: Analysis of 3,526 patients in cancer clinical trials.

e14620 Background: Immunotherapy combinations are used to improve outcomes in metastatic cancer, but knowledge of appropriate starting doses for novel combinations is lacking. Methods: Phase I-III adult combination clinical trials (≥1 drug was immunotherapy; anti-PD1, PDL1, or CTLA4) were reviewed (PubMed Jan 1, 2010 to Sep 1, 2016; ASCO 2014-2016, ASH/ESMO 2014-2015 abstracts). The safe dose used in each combination was divided by the single agent recommended dose to calculate dose percentage. Additive dose percentage was the sum of each dose percentage. Results: 84 studies (N=3,526 patients, 60 combinations) were analyzed (see Table). Eight studies had unacceptable safety: ipilimumab with cytoxan, vemurafenib, dacarbazine, dabrafenib/trametinib, or carboplatin/etoposide; nivolumab or pembrolizumab with pazopanib; and tremelimumab with sunitinib. Lowest additive dose percentages evaluated in these studies were: 160, 175, 175, 217, 300, 167, 175, and 167%; it is unclear if lower doses would have been tolerable. Combinations with ipilimumab had lower additive dose percentages. Response rates (median [interquartile range]) were higher for 3 than 2 drug combinations (53% [33%-63%] (N = 23 studies) vs. 23% [14%-39%]) (N = 60 studies) with similar rates seen for targeted, cytotoxic, or dual immunotherapy combinations. Conclusions: In 63% of studies not including ipilimumab, full doses of combinations could be given. Triplet combinations had median response rates of 53 vs. 23% for doublets (p<0.001). These findings can help inform safe starting doses for novel immunotherapy combinations in clinical trials and practice. [Table: see text]

Statistical modeling for Bayesian extrapolation of adult clinical trial information in pediatric drug evaluation.

Children represent a large underserved population of "therapeutic orphans," as an estimated 80% of children are treated off-label. However, pediatric drug development often faces substantial challenges, including economic, logistical, technical, and ethical barriers, among others. Among many efforts trying to remove these barriers, increased recent attention has been paid to extrapolation; that is, the leveraging of available data from adults or older age groups to draw conclusions for the pediatric population. The Bayesian statistical paradigm is natural in this setting, as it permits the combining (or "borrowing") of information across disparate sources, such as the adult and pediatric data. In this paper, authored by the pediatric subteam of the Drug Information Association Bayesian Scientific Working Group and Adaptive Design Working Group, we develop, illustrate, and provide suggestions on Bayesian statistical methods that could be used to design improved pediatric development programs that use all available information in the most efficient manner. A variety of relevant Bayesian approaches are described, several of which are illustrated through 2 case studies: extrapolating adult efficacy data to expand the labeling for Remicade to include pediatric ulcerative colitis and extrapolating adult exposure-response information for antiepileptic drugs to pediatrics.

Dosing Three-Drug Combinations That Include Targeted Anti-Cancer Agents: Analysis of 37,763 Patients.

Combining targeted and cytotoxic agents has the potential to improve efficacy and attenuate resistance for metastatic cancer. Information regarding safe starting doses for clinical trials of novel three-drug combinations is lacking. Published phase I-III adult oncology clinical trials of three-drug combinations involving a targeted agent were identified by PubMed search (January 1, 2010 to December 31, 2013). A dose percentage was calculated to compare the dose used in combination to the single agent recommended dose: (U.S. Food and Drug Administration-approved/recommended phase II dose/maximum tolerated dose). The additive dose percentage was the sum of the dose percentages for each drug in the combination. A total of 37,763 subjects and 243 drug combinations were included. Only 28% of studies could give each of the three agents at 100%. For combinations involving two targeted agents and a cytotoxic agent, the lowest starting additive dose percentage was 133%, which increased to 250% if two antibodies were included. For combinations of one targeted agent and two cytotoxic agents, the lowest additive safe dose percentage was 137%. When both cytotoxic agents were held at 100%, as occurred in 56% of studies (which generally used cytotoxic doublets with known combination safety dosing), the lowest safe dose percentage was 225% (providing that a histone deacetylase inhibitor was not the targeted agent). These findings serve as a safe starting point for dosing novel three-drug combinations involving a targeted agent in clinical trials and practice. The Oncologist 2017;22:576-584 IMPLICATIONS FOR PRACTICE: Targeted and cytotoxic drug combinations can improve efficacy and overcome resistance. More knowledge of safe starting doses would facilitate use of combinations in clinical trials and practice. Analysis of 37,763 subjects (243 combinations) showed three drugs could be safely administered, but less than 30% of combinations could include all three drugs at full dose. Dose reductions to 45% of the dose of each single agent may be required. Combinations involving two antibodies required fewer dose reductions, and the use of established cytotoxic doublets made initial dose assignment easier.

Reviewing concomitant medications for participants in oncology clinical trials.

The importance and key components of clinical medication reviews for participants in oncology clinical trials are described, and drug- drug interactions (DDIs) associated with new oncology drug classes are discussed. Use of investigational drugs is a mainstay of adult oncology clinical trials and has led to discovery of new oncology drug classes, including immunotherapy agents and oral targeted therapies, as well as novel chemotherapy delivery methods. As sponsor-supplied DDI information on investigational drugs and drug classes is typically limited and often inconsistent, a clinical medication review to assess the potential for DDIs is recommended for all patients enrolling in oncology clinical trials. A simplified approach to performing such reviews includes (1) evaluating the trial protocol for DDI risks, (2) meeting with the patient face-to-face to perform the review, (3) making medication-related recommendations based on the findings of the patient encounter, and (4) documenting review findings in the medical record. Pharmacists can create a personalized "concomitant-medication review guide" listing key medication-use information in table format to assist other clinicians in preventing and assessing DDIs during a patient's clinical trial participation. Each investigational drug and new drug class in oncology has a unique DDI profile. It is essential that patients be screened for DDI risks prior to clinical trial participation and that pharmacists and clinical investigators have clear guidelines for managing DDIs. Performing a clinical medication review is one approach to simplifying this process and ensuring patient safety.

Immunogenicity and safety of a cell culture-derived inactivated quadrivalent influenza vaccine (NBP607-QIV): A randomized, double-blind, multi-center, phase III clinical trial in adults and elderly subjects

ABSTRACTBackground: The influenza B virus has two lineages; Yamagata and Victoria. The two lineages are antigenically distinct and it is difficult to expect cross-protection between the lineages. Actually, the mismatch between circulating influenza B viruses and vaccine strains has been occurred frequently. The cell-culture system for the production of influenza vaccine can contribute to improve vaccine strain selection and expand vaccine supplies. We investigated the immunogenicity and safety of cell culture-derived quadrivalent inactivated influenza vaccine (NBP607-QIV) in adults and elderly subjects.Methods: A randomized controlled phase III trial was undertaken in 10 university hospitals in the Republic of Korea (Clinical trial Number—NCT02467842). Adults (aged 19–59 years) and elderly subjects (aged ≥60 years) were randomly assigned in a 2:1:1 ratio to NBP607-QIV versus cell culture-based trivalent inactivated influenza vaccine-Yamagata (NBP607-Y) and cell culture-based trivalent inactivated influenza vaccine-Victoria (NBP607-V). Immunogenicity was assessed 3 weeks after vaccination by hemagglutination inhibition assay. Safety was assessed for 6 months post-vaccination: solicited adverse events (AEs) for 7 days, unsolicited AEs for 21 days and serious adverse events (SAEs) for 6 months. AEs were sub-classified as adverse drug reactions (ADRs) according to the causality.Results: A total of 1,503 participants were randomly assigned to NBP607-QIV (n = 752), NBP607-Y (n = 373) and NBP607-V (n = 378). The seroconversion rates of NBP607-QIV were 52.4%, 51.2%, 43.7% and 55.8% against A/H1N1, A/H3N2, B/Yamagata and B/Victoria, respectively. Non-inferiority against shared strains and superiority against alternate-lineage B strains were demonstrated for NBP607-QIV vs. NBP607-Y and NBP607-V. A total of 730 reactions occurred in 324 (43.1%) subjects of NBP607-QIV group. Majority of ADRs was solicited (99.2%) and mild (90.3%) in intensity. In adults (aged 19–59 years), solicited local AEs were slightly more frequent in NBP607-QIV group than NBP607-Y or NBP607-V group (40.9%, 33.4% and 32.5%, respectively). One SAE was observed among NBP607-QIV group, which was considered to be unrelated to the study vaccine within 3 weeks of vaccination and no vaccine-related SAEs were reported up to 6 months after vaccination.Conclusions: NBP607-QIV is a safe, well-tolerated and immunogenic influenza vaccine in Korean adults and elderly subjects.

Comparison of Pharmaceutical, Psychological, and Exercise Treatments for Cancer-Related Fatigue

Cancer-related fatigue (CRF) remains one of the most prevalent and troublesome adverse events experienced by patients with cancer during and after therapy. To perform a meta-analysis to establish and compare the mean weighted effect sizes (WESs) of the 4 most commonly recommended treatments for CRF-exercise, psychological, combined exercise and psychological, and pharmaceutical-and to identify independent variables associated with treatment effectiveness. PubMed, PsycINFO, CINAHL, EMBASE, and the Cochrane Library were searched from the inception of each database to May 31, 2016. Randomized clinical trials in adults with cancer were selected. Inclusion criteria consisted of CRF severity as an outcome and testing of exercise, psychological, exercise plus psychological, or pharmaceutical interventions. Studies were independently reviewed by 12 raters in 3 groups using a systematic and blinded process for reconciling disagreement. Effect sizes (Cohen d) were calculated and inversely weighted by SE. Severity of CRF was the primary outcome. Study quality was assessed using a modified 12-item version of the Physiotherapy Evidence-Based Database scale (range, 0-12, with 12 indicating best quality). From 17 033 references, 113 unique studies articles (11 525 unique participants; 78% female; mean age, 54 [range, 35-72] years) published from January 1, 1999, through May 31, 2016, had sufficient data. Studies were of good quality (mean Physiotherapy Evidence-Based Database scale score, 8.2; range, 5-12) with no evidence of publication bias. Exercise (WES, 0.30; 95% CI, 0.25-0.36; P < .001), psychological (WES, 0.27; 95% CI, 0.21-0.33; P < .001), and exercise plus psychological interventions (WES, 0.26; 95% CI, 0.13-0.38; P < .001) improved CRF during and after primary treatment, whereas pharmaceutical interventions did not (WES, 0.09; 95% CI, 0.00-0.19; P = .05). Results also suggest that CRF treatment effectiveness was associated with cancer stage, baseline treatment status, experimental treatment format, experimental treatment delivery mode, psychological mode, type of control condition, use of intention-to-treat analysis, and fatigue measures (WES range, -0.91 to 0.99). Results suggest that the effectiveness of behavioral interventions, specifically exercise and psychological interventions, is not attributable to time, attention, and education, and specific intervention modes may be more effective for treating CRF at different points in the cancer treatment trajectory (WES range, 0.09-0.22). Exercise and psychological interventions are effective for reducing CRF during and after cancer treatment, and they are significantly better than the available pharmaceutical options. Clinicians should prescribe exercise or psychological interventions as first-line treatments for CRF.

Future directions in chimeric antigen receptor T cell therapy.

The impact of immunotherapy has grown exponentially in the past 5 years. Principle illustrations are encouraging results with engineered T cells expressing a chimeric antigen receptor (CAR). This experimental therapy is developing simultaneously in pediatric and adult clinical trials, making this field particularly relevant and exciting for pediatric oncologists. CAR-modified T cells targeting CD19 have produced dramatic antitumor responses in patients with relapsed/refractory B cell acute lymphoblastic leukemia. Clinical trials from several institutions, in both children and adults, using distinct CAR T cell products have demonstrated similar high complete remission rates of 61-93%, with durable remissions observed. Although the development of CARs for other malignancies has lagged behind, research into novel approaches to overcome inherent challenges is promising. Clinical trials of CAR-modified T cells have produced unprecedented results and are anticipated to have a broader impact as this approach expands into other indications, including other cancers and frontline therapy. The potential for long-term disease control, if fully realized, will have a transformative impact on the field.

The effects of modified ultrafiltration on clinical outcomes of adult and pediatric cardiac surgery

Abstract Background Cardiopulmonary bypass (CPB) can contribute to the development of an inflammatory response and postsurgical morbidity. Conventional ultrafiltration and modified ultrafiltration (MUF) can mitigate the adverse effects of CPB by removing free water and inflammatory mediators, at least in part. Objectives To evaluate evidence for the effects of MUF on clinical outcomes of cardiac surgery in pediatric and adult patients. Methods A literature review of MEDLINE-indexed articles published between 1990 and June 2014 was conducted on PubMed. A search on the CTS.net website and the Cochrane Central Register of Controlled Trials was also performed with relevant keywords. The search was limited to English language articles and human studies. Results Our primary search identified 84 potential articles, of which 55 articles were relevant to conventional ultrafiltration, modified ultrafiltration, ultrafiltration, cardiopulmonary bypass, extracorporeal circulation, pediatric and adult cardiac surgery. There were 3 meta-analyses, 7 review literatures, 21 randomized controlled trials. The remainder consisted of 18 controlled and 6 observational studies. MUF has been beneficial effects on postoperative bleeding, chest drainage, transfusion requirement, and improvement cardiac function, but effects in adult cardiac surgery inconclusive because data was relatively limited. Conclusions MUF may improve post-CPB hemodynamic activity and cardiac function in pediatric cardiac surgery. By contrast, the clinical trials in adults are limited mostly by small sample sizes that preclude an adequately powered assessment of clinically relevant outcomes. The available data are conflicting and several studies show no differential outcomes. Further studies are required to identify patients who will most likely benefit from ultrafiltration and to establish standard protocols.

Exosomes from pediatric dilated cardiomyopathy patients modulate a pathological response in cardiomyocytes.

Stimulation of the renin-angiotensin-aldosterone system (RAAS) and β-adrenergic receptors plays an important role in adult heart failure (HF). Despite the demonstrated benefits of RAAS inhibition and β-adrenergic receptor blockade in adult HF patients, no substantial improvement in survival rate has been observed in children with HF. This suggests that the underlying disease mechanism is uniquely regulated in pediatric HF. Here, we show that treatment of human-induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) and neonatal rat ventricular myocytes (NRVMs) with serum from pediatric dilated cardiomyopathy (DCM) patients induces pathological changes in gene expression, which occur independently of the RAAS and adrenergic systems, suggesting that serum circulating factors play an important role in cardiac remodeling. Furthermore, exosomes purified from DCM serum induced pathological changes in gene expression in NRVMs and iPSC-CMs. Our results suggest that DCM serum exosomes mediate pathological responses in cardiomyocytes and may propagate the pediatric HF disease process, representing a potential novel therapeutic target specific to this population.NEW & NOTEWORTHY The results of this work could alter the present paradigm of basing clinical pediatric heart failure (HF) treatment on outcomes of adult HF clinical trials. The use of serum-treated primary cardiomyocytes may define age-specific mechanisms in pediatric HF with the potential to identify unique age-appropriate and disease-specific therapy.

Effects of Ferric Citrate in Patients with Nondialysis-Dependent CKD and Iron Deficiency Anemia.

Iron deficiency anemia is common and consequential in nondialysis-dependent CKD (NDD-CKD). Efficacy and tolerability of conventional oral iron supplements are mixed; intravenous iron administration associates with finite but important risks. We conducted a randomized double-blind clinical trial in adults with NDD-CKD and iron deficiency anemia to compare the safety and efficacy of oral ferric citrate (n=117) and placebo (n=115). The primary end point was the proportion of patients who achieved a ≥1.0 g/dl increase in hemoglobin at any time during a 16-week randomized period. Patients who completed the 16-week period could also participate in an 8-week open-label extension period. Significantly more patients randomized to ferric citrate achieved the primary end point (61 [52.1%] versus 22 [19.1%] with placebo; P<0.001). All secondary end points reached statistical significance in the ferric citrate group, including the mean relative change in hemoglobin (0.84 g/dl; 95% confidence interval, 0.58 to 1.10 g/dl; P<0.001) and the proportion of patients who achieved a sustained increase in hemoglobin (≥0.75 g/dl over any 4-week period during the randomized trial; 57 [48.7%] versus 17 [14.8%] with placebo; P<0.001). Rates of serious adverse events were similar in the ferric citrate (12.0%) and placebo groups (11.2%). Gastrointestinal disorders were the most common adverse events, with diarrhea reported in 24 (20.5%) and 19 (16.4%) and constipation in 22 (18.8%) and 15 (12.9%) patients treated with ferric citrate and placebo, respectively. Overall, in patients with NDD-CKD, we found oral ferric citrate to be a safe and efficacious treatment for iron deficiency anemia.

Influence of Spirituality and Religion on Adherence to Highly Active Antiretroviral Therapy in Adult HIV/AIDS Patients in Calabar, Nigeria

The emergence of a chronic medical illness such as Human Immune Deficiency Virus and Acquired Immunodeficiency Syndrome (HIV/AIDS) may be the time when people turn to the Sacred through spirituality and religion. HIV is a chronic illness that requires strict adherence to medication regimens that may be influenced by spirituality/religion. This study was aimed at finding the association between spirituality/religion and adherence to highly active antiretroviral therapy (HAART) in adult HIV/AIDS patients. This is a cross-sectional descriptive study of 370 patients. Adherence was measured using an adapted adult AIDS clinical trial group (AACTG) and visual analogue scale (VAS) tools. Spirituality was assessed using Functional Assessment of Chronic Illness Therapy-Spirituality Expanded (FACIT-Sp-Ex) scale, religiosity with Duke University Religion index (DUREL), and religious coping with Brief Religious Coping (RCOPE) scale. Adherence rates were 86.2 and 43.8% using AACTG and VAS tools, respectively. Statistical significant correlation was found between spirituality and adherence to HAART (r = 0.265; p = 0.00). Also, significant correlation was found between positive religious coping and adherence (r = 0.15, p = 0.003). Odds ratio indicated that female respondents were 1.6 times more likely to be adherent, compared with males. Similarly, every unit rise in spirituality score yielded a 1.3 times increased likelihood of adherence to HAART on multiple logistic regression of adherence to HAART with relevant predictors. Both spirituality and positive religious coping have positive influence on optimal adherence. Therefore, the training of health care personnel to assess and provide spiritual care and involvement of chaplains/religious leaders is advocated for improved adherence.

Dissecting the Outcome Difference Between Children and Adolescents and Young Adults (AYAs) with Acute Lymphoblastic Leukemia (ALL)

BACKGROUNDAYAs (15-39y) with ALL have poor survival compared to children (1-14y). Placement on pediatric vs. adult clinical trials has been implicated in these differences, but a more comprehensive approach (sociodemographics, clinical prognostic factors, treatment provider/ intensity) is lacking and needs to be examined in the real world environment. We address this gap by evaluating factors contributing to the inferior outcome in AYA at a granular level.METHODS: The study included242 patients diagnosed with ALL between 1990 and 2010 at age 1-39y and treated at a comprehensive cancer center (irrespective of enrollment on clinical trial). Medical record abstraction yielded the following: Sociodemographics: payor, race/ethnicity, socioeconomic status (SES); Clinical Prognosticators: WBC at diagnosis (<100k vs. ≥100k), time between diagnosis and first clinical remission (1st CR: <5% blasts in marrow); wide temporal span precluded use of contemporary prognosticators across entire cohort; Treatment Approach: combinations of pediatric/adult oncologist and pediatric/adult therapeutic protocol (pediatric MD + pediatric protocol vs. adult MD + adult protocol vs. other); duration of treatment phases (induction, post-induction, maintenance); gaps between phases (>15d); early cessation of therapy. Using Cox regression analyses, time to relapse was evaluated from achievement of 1st CR, and censored at relapse, death, and hematopoietic cell transplantation in 1st CR or date of last contact. Five patients did not enter remission and were excluded from the analysis. We analyzed patients for two patterns of relapse: [1] Early Relapse: From 1st CR (n=237) through planned completion of therapy, with phases of therapy as time-varying covariates; [2] Late Relapse: Patients who completed treatment (n=121) were evaluated from date of last treatment until event/ follow-up. RESULTSClinical and demographic characteristics were similar between AYAs (n=142) and children (n=95) [non-white race/ethnicity: 67% vs. 66%, p=0.9; public insurance: 39% vs. 34%, p=0.4; WBC>100K 27% vs. 20%, p=0.2; median time to remission: 31d vs. 31d, p=0.91). However, AYAs received fewer months of maintenance therapy than children (median=14.9m vs 24.8m, p<0.001). AYAs experienced poorer relapse-free survival (5y RFS: 46%, 95%CI 38-55%) vs. children (72%, 95%CI 63-80%; p<0.001) (Figure)Early Relapse: Compared with children, AYAs had a 6-fold higher risk of relapse (HR=6.0, 95%CI 3.2-11.3, p<0.001). In a multivariable model (adjusting for gender, race/ ethnicity, payor, WBC, time to 1st CR, gaps in treatment, early cessation of therapy and physician/ therapy), the risk of relapse was partially mitigated, (HR=3.8, 95%CI 1.6-9.4, p=0.003). Other variables independently associated with relapse included months to 1st CR (HR=2.1, 95%CI 1.4-3.0, p<0.001); treatment gap (HR=5.8, 95%CI 2.4-14.3, p<0.001); early cessation of therapy (HR=3.6, 95%CI 1.2-11.4, p=0.03); and high WBC (HR=2.0, 95%CI 1.2-3.5, p=0.01). Late Relapse: In patients who completed therapy (n=121), multivariable analysis revealed a higher risk of relapse (HR=2.9, 95%CI 0.9-9.1, p=0.07) for AYAs, adjusting for gender, race/ ethnicity, payor, SES, duration of treatment phases, high WBC, time to achieve remission and physician/ therapy. The only other variable associated with relapse risk was duration of maintenance in months; longer duration of maintenance was protective (HR=0.9, 95%CI 0.8-0.95, p<0.001). CONCLUSIONSSeveral factors explain, in part, the poor early outcome among AYAs, including longer time to remission, longer gaps between phases and early cessation of therapy. Among those who complete all phases of therapy, AYAs continue to have inferior outcomes, but the magnitude of difference is reduced, and duration of maintenance therapy remains the critical independent predictor of relapse risk. These findings highlight the need to elucidate the remaining factors that could explain the difference in outcome between AYAs and children, such as host and disease biology, and adherence to prescribed therapy; these are currently under investigation. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Bromodomain and extraterminal protein inhibitors in pediatrics: A review of the literature.

The last few years have seen the identification of pharmacologic approaches to target bromodomain and extraterminal (BET) proteins for cancer treatment. These proteins have an essential role in gene transcription regulation by binding acetylated lysine residues on histone tails, activating gene transcription. BET inhibitors have been tested in preclinical models including pediatric malignancies and several adult clinical trials are ongoing. Since the development of new drugs in pediatric cancer has long lagged behind programs for adults, the aim of this review is to show the importance of these therapies in pediatric malignancies to support their development in pediatric oncology/hematology.

Abstract A051: Characterization of IDO1 and TDO2 in pediatric central nervous system tumors

Abstract Purpose: Indoleamine 2,3 dioxygenase 1 (IDO1) and tryptophan dioxygenase (TDO2) are tryptophan catabolic enzymes that have been implicated in facilitating immunosuppression in cancer. With respect to the central nervous system (CNS), both enzymes have been correlated with decreased overall survival in adult patients with glioma. Based on these observations, we questioned whether pediatric CNS tumors, which constitute the most common form of solid cancer in children, also possess expression and activity for these immunosuppressive mediators. Experimental Design: Purified RNA from pediatric patient tumor tissue was obtained from the Children's Brain Tumor Tissue Consortium (Philadelphia, PA) and utilized for qRT-PCR analysis of IDO1, TDO2, CD3e, IFNγ, and TGFβ1. Primary cell lines were propagated from fresh tumor tissue acquired by Dr. Rintaro Hashizume, Ph.D. (Northwestern University) and cultured for 48 hours alone or with a combination of 100 ng/mL IFNγ and 10, 50, 250 or 1000 nM L1MT, D1MT and BGB-5777; a novel pharmaceutical-grade IDO1 inhibitor (Beigene). Cell culture supernatants were collected at 48 hours for detection of tryptophan (Trp) and kynurenine (Kyn) levels by high pressure liquid chromatography. The cells were collected confirmed for IDO1 protein expression via western blot. Results: RT-PCR defined two populations of pediatric high grade glioma (HGG) based on high (&amp;gt;3 fold expression compared to average) versus low (&amp;lt;3 fold expression compared to average) IDO1-expressing tumors. In contrast, low grade glioma (LGG) and diffuse intrinsic pontine glioma (DIPG) universally expressed low IDO1 levels when compared to HGG. All patient tumors expressed TDO2 mRNA. All tumors were infiltrated by T cells, based on the ubiquitous presence of CD3ϵ mRNA. Primary human pediatric cell lines comprised of HGG and DIPG inducibly expressed IDO1 mRNA and protein after treatment IFNγ (P &amp;lt; 0.001). Unexpectedly, IFNγ treatment also led to increased TDO2 mRNA expression in DIPG cells. To determine whether these enzymes were functionally active, BGB-5777, in addition to historical IDO1 pathway modulators, L1-MT and D1-MT, were co-incubated with the pediatric cell lines plus IFNγ. At 250 nM, BGB-5777 significantly decreased the Kyn/Trp ratio in both HGG and DIPG cell lines (p&amp;lt;0.001), while treatment with L1-MT and D1-MT concentrations had no impact. Conclusion: These data show for the first time that, IDO1 is expressed in pediatric tumors and the novel blood brain barrier-penetrating IDO1 inhibitor, BGB-5777, is a highly potent inhibitor of enzymatic activity in this setting. Given that IDO1 inhibitors are already in multiple clinical trials for adults with brain cancer, these data suggest that BGB-5777 may be a valuable tool for inhibiting IDO1 in the setting of malignant pediatric brain cancer. Citation Format: Kristen Lauing, Rishi Lulla, Lijie Zhai, Rintaro Hashizume, Jason Fangusaro, Derek A. Wainwright. Characterization of IDO1 and TDO2 in pediatric central nervous system tumors [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr A051.

207 - Incidence and Etiology of Unplanned Reoperations following Index Surgery in the Adult Symptomatic Lumbar Scoliosis NIH-Sponsored Clinical Trial

207 - Incidence and Etiology of Unplanned Reoperations following Index Surgery in the Adult Symptomatic Lumbar Scoliosis NIH-Sponsored Clinical Trial

Clinical Drug Development in Epilepsy Revisited: A Proposal for a New Paradigm Streamlined Using Extrapolation.

Data from clinical trials in adults, extrapolated to predict benefits in paediatric patients, could result in fewer or smaller trials being required to obtain a new drug licence for paediatrics. This article outlines the place of such extrapolation in the development of drugs for use in paediatric epilepsies. Based on consensus expert opinion, a proposal is presented for a new paradigm for the clinical development of drugs for focal epilepsies. Phase I data should continue to be collected in adults, and phase II and III trials should simultaneously recruit adults and paediatric patients aged above 2 years. Drugs would be provisionally licensed for children subject to phase IV collection of neurodevelopmental safety data in this age group. A single programme of trials would suffice to license the drug for use as either adjunctive therapy or monotherapy. Patients, clinicians and sponsors would all benefit from this new structure through cost reduction and earlier access to novel treatments. Further work is needed to elicit the views of patients, their parents and guardians as appropriate, regulatory authorities and bodies such as the National Institute for Health and Care Excellence (UK).

Binocular low-contrast letter acuity and the symbol digit modalities test improve the ability of the Multiple Sclerosis Functional Composite to predict disease in pediatric multiple sclerosis

BackgroundOutcome measures to capture disability, such as the Multiple Sclerosis Functional Composite (MSFC), were developed to enhance outcome measurements for clinical trials in adults with multiple sclerosis (MS). The MSFC initially included three components: a timed 25-foot walk [T25FW], 9-hole peg test [9HPT], and the Paced Auditory Serial Addition Task [PASAT]. Modifications to the original MSFC, such as adding binocular low-contrast letter acuity (LCLA) or substituting the symbol digit modalities test (SDMT) for the PASAT, improved the capacity to capture neurologic impairment in adults. Similar outcome scales for pediatric MS have not yet been established. ObjectiveTo determine whether the three-component MSFC or a modified MSFC with LCLA and the SDMT better identifies neurological deficits in pediatric MS. MethodsWe evaluated 5 measures (T25FW, 9HPT, Children's PASAT [ChiPASAT], SDMT, and binocular LCLA [Sloan charts, 1.25% contrast]) in children with MS (disease onset <18 years) and healthy controls. To be able to compare measures whose scores have different scales, Z-scores were also created for each test based on the numbers of standard deviations from a control group mean, and these individual scale scores were combined to create composite scores. Logistic regression models, accounting for age, were used to determine whether the standard 3-component MSFC or modified versions (including 4 or 5 metrics) best distinguished children with MS from controls. ResultsTwenty pediatric-onset MS subjects, aged 6–21 years, and thirteen healthy controls, aged 6–19 years, were enrolled. MS subjects demonstrated worse scores on the 9HPT (p=0.004) and SDMT (p=0.001), but not the 25FTW (adjusted for height, p=0.63) or the ChiPASAT (p=0.10): all comparisons adjusted for age. Decreased (worse) binocular LCLA scores were associated with MS (vs. control status, p=0.03, logistic regression; p=0.08, accounting for age). The MSFC composite score for the traditional 3 components did not differ between the groups (p=0.28). Replacing the ChiPASAT with the SDMT (OR 0.72, p=0.05) better distinguished MS from controls. A modified MSFC-4 with the SDMT replacing the ChiPASAT and including binocular 1.25% LCLA had the greatest capacity to distinguish pediatric MS from controls (OR 0.89, p=0.04, logistic regression). Including all 5 metrics as a composite MSFC-5 did not improve the model (p=0.18). ConclusionsA modified MSFC (25FTW, 9HPT, SMDT, and binocular 1.25% LCLA) is more sensitive than the traditional MSFC or its components to capture the subtle impairments that characterize pediatric MS and should be validated in order to be considered for future pediatric MS trials.

372 The effect of dupilumab on biomarkers in a randomized phase 2b clinical trial in adults with moderate-to-severe atopic dermatitis

372 The effect of dupilumab on biomarkers in a randomized phase 2b clinical trial in adults with moderate-to-severe atopic dermatitis

Blood pressure variability and cardiovascular disease: systematic review and meta-analysis

Objective To systematically review studies quantifying the associations of long term (clinic), mid-term (home), and short term (ambulatory) variability in blood pressure, independent of mean blood pressure, with cardiovascular disease...